In recent years, it has become accepted that immune cells play an active role in atherogenesis. Through various mouse studies, different subsets of lymphocytes have been shown to contribute to the atherosclerotic burden. However, mechanisms for how these cells contribute to atherogenesis or atheroprotection are not clearly understood. Moreover, an emerging concept is that lymphocytes and macrophages must communicate in the artery wall, but how this crosstalk influences atherogenesis is not clearly defined. In this PPG, we will study the immunobiology of atherosclerosis, with the goal of understanding how macrophages and lymphocytes communicate in the aortic wall to odulate atherogenesis. The PPG is comprised of three Projects and two Cores. In Project 1, Dr Hedrick will investigate how T regulatory lymphocyte function is changed during atherogenesis and subjects with Type 2 diabetes. In Project 2, Drs. Miller and Witztum will investigate how oxidized cholesteryl esters modulate TLR signaling in macrophages to influence metabolic endotoxemia and atherogenesis. Project 3 (McNamara) will study how B cells confer atheroprotection, and how the ranscriptional repressor Id3 influences B cell function in the aortic wall. The development of these projects involves extensive collaborations among all investigators. The Projects will be supported by two Cores, an Administrative Core and a Human Phenotyping and Immune Cell Core. This Human Core provides a translational aspect to our Program, providing blood samples, extensive subject phenotyping, and atherosclerosis assessment for subjects with and without Type 2 diabetes. As cardiovascular disease is a major risk factor for subjects with Type 2 diabetes, having access to such samples is a unique translational opportunity for our Program. Each project will utilize the Human Core to study immune cells from human subjects to establish functional links between candidate genes of interest and immune cell function in atherogenesis.